盐酸地芬诺酯 | 915-30-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 盐酸地芬诺酯
• 中文别名: 止泻宁；苯乙哌啶；1-(3,3-二苯基-3-氰基丙基)-4-苯基-4-哌啶甲酸乙酯；地芬诺酯；盐酸苯乙哌啶；地酚诺酯
• 英文名称: lomotil
• 英文别名: diphenoxylate；1-(3-cyano-3,3-diphenyl-propyl)-4-phenyl-piperidine-4-carboxylic acid ethyl ester；1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester；4-(4-Phenyl-4-ethoxycarbonyl-piperidino)-2,2-diphenyl-buttersaeurenitril；ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate
• CAS: 915-30-0
• 化学式: C₃₀H₃₂N₂O₂
• 分子量: 452.596
• InChiKey: HYPPXZBJBPSRLK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  53.3
• 氢给体数：
  0
• 氢受体数：
  4

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

双苯氧基醋酸在大鼠和狗中产生1-(3-氰基-3,3-二苯基丙基)-4-苯基异尼泊酸酯。/来自表格/

DIPHENOXYLATE YIELDS 1-(3-CYANO-3,3-DIPHENYLPROPYL)-4-PHENYLISONIPECOTIC ACID IN RATS & DOGS. /FROM TABLE/

来源:Hazardous Substances Data Bank (HSDB)

代谢

... 二苯甲氧基的主要代谢反应在人类和其他物种中是水解，产生大量的二苯甲氧基 ...

... MAIN METABOLIC REACTION /OF DIPHENOXYLATE/ IN MAN & OTHER SPECIES IS HYDROLYSIS TO YIELD LARGE AMT OF DIFENOXINE ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

肝脏生物转化；主要代谢物双苯氧酸（二苯氧基酸）具有相似活性。

Hepatic biotransformation; the major metabolic difenoxin (diphenoxylic acid) has similar activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

双苯氧基酸是一种活性代谢物。该药物还代谢生成羟基双苯氧基酸。双苯氧基酸代谢物及其结合物缓慢排出，主要随胆汁通过粪便排出；较少量通过尿液排出。少于1%以原形通过尿液排出。

Diphenoxylate is rapidly and extensively metabolized to diphenoxylic acid, an active metabolite. The drug is also metabolized to hydroxydiphenoxylic acid. Diphenoxylate metabolites and their conjugates are slowly excreted, principally in feces via bile; lesser amounts are excreted in urine. Less than 1% is exceted unchanged in urine.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

双苯氧基酸是一种激动μ受体的阿片受体激动剂，在胃肠道中减少蠕动并收缩括约肌。双苯氧基酸对肠道的环形平滑肌有直接作用，可能导致肠道内容的分段和胃肠道传输时间的延长。因此，双苯氧基酸的临床抗腹泻作用可能是由于增强的分段作用，这使得肠道内容物与肠粘膜的接触增加。

Diphenoxylate is an opiate receptor agonists that stimulate mu receptors in GI to decrease the peristalsis and constrict the sphincters. Diphenoxylate has a direct effect on circular smooth muscle of the bowel, that conceivably results in segmentation and prolongation of gastrointestinal transit time. The clinical antidiarrheal action of diphenoxylate may thus be a consequence of enhanced segmentation that allows increased contact of the intraluminal contents with the intestinal mucosa.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

目前使用的绝大多数阿片类药物一样，阿托品与双苯氧基酸酯的治疗并未与血清酶水平升高有关联。尚无确凿病例表明双苯氧基酸酯引起了特异质急性、临床上明显的肝损伤。其缺乏肝毒性的原因可能与使用的低剂量有关。被吸收的双苯氧基酸酯在肝脏中代谢。 关于双苯氧基酸酯的安全性和潜在肝毒性的参考资料，请参见阿片类药物概述部分。 药物类别：胃肠药；阿片类药物

As with most opiates in current use, therapy with diphenoxylate with atropine has not been linked to serum enzyme elevations. There have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to diphenoxylate. The reason for its lack of hepatotoxicity may relate partially to the low doses used. What diphenoxylate that is absorbed is metabolized in the liver. References on the safety and potential hepatotoxicity of diphenoxylate are given in the Overview section of the Opioids. Drug Class: Gastrointestinal Agents; Opioids

来源:LiverTox

毒理性

• 药物性肝损伤

药物名称：双苯氧基醋酸酯

Compound:diphenoxylate

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注释：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

百分之九十

90%

来源:DrugBank

吸收、分配和排泄

粪便/肾脏排泄；少于1%以原形在尿液中排出。

Fecal/renal elimination; less than 1% eliminated unchanged in urine.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

在一项针对禁食个体的研究中，双苯氧基醋酸氢氯化物在口服给药后从胃肠道良好吸收，该药物是以酒精溶液形式给药，未添加硫酸阿托品。给药后约2小时，血浆中双苯氧基醋酸浓度达到峰值。在一项交叉生物利用度研究中，比较了洛莫替尔片剂和口服溶液，片剂的生物利用度约为溶液的90%；在口服四片2.5毫克片剂后，大约2小时内，平均血浆中双苯氧基醋酸（双苯氧基醋酸的一个活性代谢物）的峰值浓度为163纳克/毫升。双苯氧基醋酸的起效时间在45分钟到1小时之间，作用持续时间为3-6小时。/双苯氧基醋酸氢氯化物/

In one study in fasting individuals, diphenoxylate hydrochloride was well absorbed from the GI tract following oral administration of an alcoholic solution of the drug without atropine sulfate. Peak plasma diphenoxylate concentrations occurred about 2 hours following administration of the drug. In a crossover bioavailability study of Lomotil tablets and oral solution, the bioavailability of the tablets was approximately 90% that of the solution; following an oral dose of four 2.5 mg tablets, an average peak plasma concentraton of diphenoxylic acid (an active metabolite of diphenoxylate) of 163 ng/ml occurred within about 2 hours. Diphenoxylate had an onset of action within 45 minutes to 1 hour and a duration of action of 3-6 hours. /Diphenoxylate hydrochloride/

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

双苯氧基醋酸会分布到乳汁中。

Diphenoxylate is distributed into milk.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

双苯氧基酸是一种活性代谢物。该药物还代谢生成羟基双苯氧基酸。双苯氧基酸代谢物及其结合物缓慢排出，主要随胆汁通过粪便排出；较少量通过尿液排出。少于1%以原形通过尿液排出。

Diphenoxylate is rapidly and extensively metabolized to diphenoxylic acid, an active metabolite. The drug is also metabolized to hydroxydiphenoxylic acid. Diphenoxylate metabolites and their conjugates are slowly excreted, principally in feces via bile; lesser amounts are excreted in urine. Less than 1% is exceted unchanged in urine.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  乙酸酐 、 盐酸地芬诺酯 生成 1-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-3,3-diphenyl-propyl]-4-phenyl-piperidine-4-carboxylic acid ethyl ester
  参考文献：
  名称：

  3,3-Diphenyl-3-(2-alkyl-1,3,4-oxadiazol-5-yl)propylcycloalkylamines, a novel series of antidiarrheal agents

  摘要：

  A series of 4-amino-2,2-diarylbutyronitriles (3) prepared for testing as inhibitors of gastrointestinal propulsive activity did not show any enhancement over such existing agents as diphenoxylate and loperamide. However, conversion of the nitrile group to a 2-methyl-1,3,4-oxadiazol-5-yl function led to compounds 5g and 5j, statistically equipotent to diphenoxylate and loperamide in the mouse and showing a very low order of analgesic activity. Structural modifications determined that the best separation of antipropulsive and analgesic effects was obtained when the amino group was bicyclic and the oxadiazole ring had a 2-methyl substituent. The most potent compounds were and analogues of diphenoxylate and loperamide where the oxadiazole ring was present, but these compounds had marked analgesic activity.

  DOI：

  10.1021/jm00232a010

文献信息

• IRAK DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20190192668A1

  公开（公告）日：2019-06-27

  The present invention provides compounds, compositions thereof, and methods of using the same.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。
• [EN] LYMPHATIC SYSTEM-DIRECTING LIPID PRODRUGS<br/>[FR] PROMÉDICAMENTS LIPIDIQUES ORIENTANT VERS LE SYSTÈME LYMPHATIQUE
  申请人：ARIYA THERAPEUTICS INC

  公开号：WO2019046491A1

  公开（公告）日：2019-03-07

  The present invention provides lymphatic system-directing lipid prodrugs, pharmaceutical compositions thereof, methods of producing such prodrugs and compositions, as well as methods of improving the bioavailability or other properties of a therapeutic agent that comprises part of the lipid prodrug. The present invention also provides methods of treating a disease, disorder, or condition such as those disclosed herein, comprising administering to a patient in need thereof a provided lipid prodrug or a pharmaceutical composition thereof.

  本发明提供了淋巴系统定向脂质前药，其制药组合物，制备这种前药和组合物的方法，以及改善作为脂质前药一部分的治疗剂的生物利用度或其他性质的方法。本发明还提供了治疗疾病、紊乱或症状的方法，包括向需要的患者施用所提供的脂质前药或其制药组合物。
• [EN] IRAK DEGRADERS AND USES THEREOF<br/>[FR] AGENTS DE DÉGRADATION D'IRAK ET LEURS UTILISATIONS
  申请人：KYMERA THERAPEUTICS INC

  公开号：WO2020264499A1

  公开（公告）日：2020-12-30

  The present invention provides compounds, compositions thereof, and methods of using the same. The compounds include an IRAK binding moiety capable of binding to IRAK4 and a degradation inducing moiety (DIM). The DIM could be DTM a ligase binding moiety (LBM) or lysine mimetic. The compounds could be useful as IRAK protein kinase inhibitors and applied to IRAK mediated disorders.

  本发明提供了化合物、其组合物以及使用这些化合物的方法。这些化合物包括能够结合到IRAK4的IRAK结合基团和诱导降解的基团（DIM）。DIM可以是DTM、一个连接酶结合基团（LBM）或赖氨酸类似物。这些化合物可以作为IRAK蛋白激酶抑制剂，并应用于IRAK介导的疾病。
• [EN] TRICYCLIC MODULATORS OF TNF SIGNALING<br/>[FR] MODULATEURS TRICYCLIQUES DE LA SIGNALISATION DU TNF
  申请人：ABBVIE INC

  公开号：WO2016168641A1

  公开（公告）日：2016-10-20

  The invention provides tricyclic heterocyclic compounds, pharmaceutically acceptable salts, prodrugs, biologically active metabolites, stereoisomers and isomers thereof wherein the variables are defined herein. The compounds of the invention may be useful for treating immunological and oncological conditions.

  这项发明提供了三环杂环化合物，其药用盐、前药、生物活性代谢物、立体异构体和同分异构体，其中变量在此处定义。该发明的化合物可能对治疗免疫和肿瘤疾病有用。
• 3,4,6-Substituted pyridazines for treating neuropathic pain and associated syndromes
  申请人：Sultzbaugh Lance

  公开号：US20070191365A1

  公开（公告）日：2007-08-16

  The present invention is directed to the use of 3,4,6-substituted pyridazines such as those characterized by structure I for treating conditions such as neuropathic pain among others.

  本发明涉及使用3,4,6-取代吡啶嗪，如结构I所示的化合物，用于治疗神经病痛等疾病。